Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3, 165-183 (1991) and Murphy, Rev. Immun., 12, 593-633 (1994)). There are two classes of chemokines, C-X-C (xcex1) and C-C (xcex2), depending on whether the first two cysteines are separated by a single amino acid (C-X-C) or are adjacent (C-C). The xcex1-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils, whereas xcex2-chemokines, such as RANTES, MIP-1xcex1, MIP-1xcex2, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Nature, 381, 661-666 (1996)).
The chemokines bind specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed xe2x80x9cchemokine receptors.xe2x80x9d On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least seven human chemokine receptors that bind or respond to xcex2-chemokines with the following characteristic pattern: CCR-1 (or xe2x80x9cCKR-1xe2x80x9d or xe2x80x9cCC-CKR-1xe2x80x9d) [MIP-1xcex1, MIP-1xcex2, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem., 270, 22123-22128 (1995); Beote, et al, Cell, 72, 415-425 (1993)); CCR-2A and CCR-2B (or xe2x80x9cCKR-2Axe2x80x9d/xe2x80x9cCKR-2Axe2x80x9d or xe2x80x9cCC-CKR-2Axe2x80x9d/xe2x80x9cCC-CKR-2Axe2x80x9d) [MCP-1, MCP-3, MCP-4]; CCR-3 (or xe2x80x9cCKR-3xe2x80x9d or xe2x80x9cCC-CKR-3xe2x80x9d) [eotaxin, RANTES, MCP-3] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995); CCR-4 (or xe2x80x9cCKR-4xe2x80x9d or xe2x80x9cCC-CKR-4xe2x80x9d) [MIP-1xcex1, RANTES, MCP-1] (Power, et al., J. Biol. Chem., 270, 19495-19500 (1995)); CCR-5 (or xe2x80x9cCKR-5xe2x80x9d or xe2x80x9cCC-CKR-5xe2x80x9d) [MIP-1xcex1, RANTES, MIP-1xcex2] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); and the Duffy blood-group antigen [RANTES, MCP-1] (Chaudhun, et al., J. Biol. Chem., 269, 7835-7838 (1994)). The xcex2-chemokines include eotaxin, MIP (xe2x80x9cmacrophage inflammatory proteinxe2x80x9d), MCP (xe2x80x9cmonocyte chemoattractant proteinxe2x80x9d) and RANTES (xe2x80x9cregulation-upon-activation, normal T expressed and secretedxe2x80x9d).
Chemokine receptors, such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases.
A retrovirus designated human immunodeficiency virus (HIV-1) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV.
Certain compounds have been demonstrated to inhibit the replication of HIV, including soluble CD4 protein and synthetic derivatives (Smith, et al., Science, 238, 1704-1707 (1987)), dextran sulfate, the dyes Direct Yellow 50, Evans Blue, and certain azo dyes (U.S. Pat. No. 5,468,469). Some of these antiviral agents have been shown to act by blocking the binding of gp120, the coat protein of HIV, to its target, the CD4 gyycoprotein of the cell.
Entry of HIV-1 into a target cell requires cell-surface CD4 and additional host cell cofactors. Fusin has been identified as a cofactor required for infection with virus adapted for growth in transformed T-cells, however, fusin does not promote entry of macrophagetropic viruses which are believed to be the key pathogenic strains of HIV in vivo. It has recently been recognized that for efficient entry into target cells, human immunodeficiency viruses require the chemokine receptors CCR-5 and CXCR-4, as well as the primary receptor CD4 (Levy, N. Engl. J. Med., 335(20), 1528-1530 (Nov. 14 1996). The principal cofactor for entry mediated by the envelope glycoproteins of primary macrophage-trophic strains of HIV-1 is CCR5, a receptor for the xcex2-chemokines RANTES, MIP-1xcex1 and MIP-1xcex2 (Deng, et al., Nature, 381, 661-666 (1996)). HIV attaches to the CD4 molecule on cells through a region of its envelope protein, gp120. It is believed that the CD-4 binding site on the gp120 of HIV interacts with the CD4 molecule on the cell surface, and undergoes conformational changes which allow it to bind to another cell-surface receptor, such as CCR5 and/or CXCR-4. This brings the viral envelope closer to the cell surface and allows interaction between gp41 on the viral envelope and a fusion domain on the cell surface, fusion with the cell membrane, and entry of the viral core into the cell. Macrophage-tropic HIV and SIV envelope proteins have been shown to induce a signal through CCR-5 on CD4+ cells resulting in chemotaxis of T cells which may enhance the replication of the virus (Weissman, et al., Nature, 389, 981-985 (1997)). It has been shown that xcex2-chemokine ligands prevent HIV-1 from fusing with the cell (Dragic, et al., Nature, 381, 667-673 (1996)). It has further been demonstrated that a complex of gp120 and soluble CD4 interacts specifically with CCR-5 and inhibits the binding of the natural CCR-5 ligands MIP-1xcex1, and MIP-1xcex2 (Wu, et al., Nature, 384, 179-183 (1996); Trkola, et al., Nature, 384, 184-187 (1996)).
Humans who are homozygous for mutant CCR-5 receptors which do not serve as co-receptors for HIV-1 in vitro apper to be unusually resistant to HIV-1 infection and are not immuno-compromised by the presence of this genetic variant (Nature, 382, 722-725 (1996)). Similarly, an alteration in the CCR-2 gene, CCR2-64I, can prevent the onset of full-blown AIDS (Smith, et al., Science, 277, 959-965 (1997). Absence of CCR-5 appears to confer protection from HIV-1 infection (Nature, 382, 668-669 (1996)). An inherited mutation in the gene for CCR5, Delta 32, has been shown to abolish functional expression of the gene and individuals homozygous for the mutation are apparently not susceptible to HIV infection. Other chemokine receptors may be used by some strains of HIV-1 or may be favored by non-sexual routes of transmission. Although most HIV-1 isolates studied to date utilize CCR-5 or fusin, some can use both as well as the related CCR-2B and CCR-3 as co-receptors (Nature Medicine, 2(11), 1240-1243 (1996)). Nevertheless, drugs targeting chemokine receptors may not be unduly compromised by the genetic diversity of HIV-1 (Zhang, et al., Nature, 383, 768 (1996)). The xcex2-chemokine macrophage-derived chemokine (MDC) has been shown to inhibit HIV-1 infection (Pal, et al., Science, 278 (5338), 695-698 (1997). The chemokines RANTES, MIP-1xcex1, MIP-1xcex2, vMIP-I, vMIP-II, SDF-1 have also been shown to suppress HIV. A derivative of RANTES, (AOP)-RANTES, is a subnanomolar antagonist of CCR-5 function in monocytes (Simmons, et al., Science, 276, 276-279 (1997)). Monoclonal antibodies to CCR-5 have been reported to block infection of cells by HIV in vitro. Accordingly, an agent which could block chemokine receptors in humans who possess normal chemokine receptors should prevent infection in healthy individuals and slow or halt viral progression in infected patients (see Science, 275, 1261-1264 (1997)). By focusing on the host""s cellular immune response to HIV infection, better therapies towards all subtypes of HIV may be provided. These results indicate that inhibition of chemokine receptors presents a viable method for the prevention or treatment of infection by HIV and the prevention or treatment of AIDS.
The peptides eotaxin, RANTES, MIP-1xcex1, MIP-1xcex2, MCP-1, and MCP-3 are known to bind to chemokine receptors. As noted above, the inhibitors of HIV-1 replication present in supernatants of CD8+ T cells have been characterized as the xcex2-chemokines RANTES, MIP-1xcex1 and MIP-1xcex2. PCT Patent Publication WO 97/10211 and EPO Patent Publication EP 0,673,928 disclose certain piperidines as tachykinin antagonists. PCT Patent Publications WO 97/24325 and WO 97/44329, and Japan Patent Publication JP 09,249,566 disclose certain compounds as chemokine antagonists.
The present invention is directed to compounds which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.
The present invention is further concerned with compounds which inhibit the entry of human immunodeficiency virus (HIV) into target cells and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the prevention and/or treatment of the resulting acquired immune deficiency syndrome (AIDS). The present invention also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the prevention and treatment of AIDS and viral infection by HIV.
The present invention is directed to compounds of formula I: 
wherein:
R1 is selected from a group consisting of:
linear or branched C1-8 alkyl, linear or branched C2-8 alkenyl,
xe2x80x83wherein the C1-8 alkyl or C2-8 alkenyl is optionally mono, di, tri or tetra substituted, where the substituents are independently selected from:
(a) hydroxy,
(b) oxo,
(c) cyano,
(d) halogen which is selected from F, Cl, Br, and I,
(e) trifluoromethyl,
(f) phenyl
(g) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(1xe2x80x2) phenyl,
(2xe2x80x2) hydroxy,
(3xe2x80x2) C1-6alkyl,
(4xe2x80x2) cyano,
(5xe2x80x2) halogen,
(6xe2x80x2) trifluoromethyl,
(7xe2x80x2) xe2x80x94NR6COR7,
(8xe2x80x2) xe2x80x94NR6CO2R7,
(9xe2x80x2) xe2x80x94NR6CONHR7,
(10xe2x80x2) xe2x80x94NR6S(O)jR7, wherein j is 1 or 2,
(11xe2x80x2) xe2x80x94CONR6R7,
(12xe2x80x2) xe2x80x94COR6,
(13xe2x80x2) xe2x80x94CO2R6,
(14xe2x80x2) xe2x80x94OR6,
(15xe2x80x2) xe2x80x94S(O)kR6, wherein k is 0, 1 or 2,
(h) xe2x80x94NR6R7,
(i) xe2x80x94NR6COR7,
(j) xe2x80x94NR6CO2R7,
(k) xe2x80x94NR6CONHR7,
(l) xe2x80x94NR6S(O)j-R7,
(m) xe2x80x94CONR6R7,
(n) xe2x80x94COR7,
(o) xe2x80x94CO2R7,
(p) xe2x80x94OR7,
(q) xe2x80x94S(O)kR7,
(r) xe2x80x94NR6CO-heteroaryl,
(s) xe2x80x94NR6S(O)j-heteroaryl, and
(t) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1xe2x80x2) benzimidazolyl,
(2xe2x80x2) benzofuranyl,
(3xe2x80x2) benzoxazolyl,
(4xe2x80x2) furanyl,
(5xe2x80x2) imidazolyl,
(6xe2x80x2) indolyl,
(7xe2x80x2) isooxazolyl,
(8xe2x80x2) isothiazolyl,
(9xe2x80x2) oxadiazolyl,
(10xe2x80x2) oxazolyl,
(11xe2x80x2) pyrazinyl,
(12xe2x80x2) pyrazolyl,
(13xe2x80x2) pyridyl,
(14xe2x80x2) pyrimidyl,
(15xe2x80x2) pyrrolyl,
(16xe2x80x2) quinolyl,
(17xe2x80x2) tetrazolyl,
(18xe2x80x2) thiadiazolyl,
(19xe2x80x2) thiazolyl,
(20xe2x80x2) thienyl, and
(21xe2x80x2) triazolyl,
xe2x80x83wherein the heteroaryl is unsubstituted or mono di or tri-substituted, where the substituents are independently selected from:
(axe2x80x3) phenyl,
(bxe2x80x3) hydroxy,
(cxe2x80x3) oxo,
(dxe2x80x3) cyano,
(exe2x80x3) halogen,
(fxe2x80x3) C1-6alkyl,and
(gxe2x80x3) trifluoromethyl;
R2 is selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) C1-6alkyl,
(4) substituted C1-6 alkyl, where the substituents are independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
(d) halogen,
(e) trifluoromethyl,
(f) xe2x80x94N(R4)(R5), wherein R4 and R5 are independently selected from hydrogen, C1-6 alkyl, and C1-6 alkyl substituted with C5-8 cycloalkyl,
(g) xe2x80x94N(R4)xe2x80x94COxe2x80x94Oxe2x80x94(R5), and
(h) xe2x80x94N(R4xe2x80x2)xe2x80x94COxe2x80x94N(R4)(R5), wherein R4 is selected from the definitions of R4,
(5) xe2x80x94Oxe2x80x94C1-6 alkyl, and
(6) phenyl;
R3 is selected from the group consisting of:
(1) xe2x80x94N(R8)xe2x80x94COxe2x80x94Oxe2x80x94(C1-6 alkyl)xe2x80x94Ar, and
(2) xe2x80x94N(R8)xe2x80x94COxe2x80x94Oxe2x80x94R7;
Ar is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyrimidyl,
(4) naphthyl,
(5) furyl,
(6) pyrryl,
(7) thienyl,
(8) isothiazolyl,
(9) imidazolyl,
(10) benzimidazolyl,
(11) tetrazolyl,
(12) pyrazinyl,
(13) quinolyl,
(14) isoquinolyl,
(15) benzofuryl,
(16) isobenzofuryl,
(17) benzothienyl,
(18) pyrazolyl,
(19) indolyl,
(20) isoindolyl,
(21) purinyl,
(22) isoxazolyl,
(23) thiazolyl,
(24) oxazolyl,
(25) triazinyl, and
(26) benzthiazolyl,
(27) benzoxazolyl,
(28) imidazopyrazinyl,
(29) triazolopyrazinyl,
(30) naphthyridinyl,
(31) furopyridinyl,
(32) thiopyranopyrimidyl and the 5-oxide and 5-dioxide thereof,
(33) pyridazinyl,
(34) quinazolinyl,
(35) pteridinyl,
(36) triazolopyrimidyl,
(37) triazolopyrazinyl,
(38) thiapurinyl,
(39) oxapurinyl, and
(40) deazapurinyl,
xe2x80x83wherein Ar items (1) to (40) are unsubstituted or mono or di-substituted, where the substituents are independently selected from:
(a) C1-6 alkyl, unsubstituted or substituted with a substituent selected from:
(1xe2x80x2) oxo,
(2xe2x80x2) hydroxy,
(3xe2x80x2)xe2x80x94OR7,
(4xe2x80x2) phenyl,
(5xe2x80x2) trifluoromethyl, and
(6xe2x80x2) phenyl or mono, di or tri-substituted phenyl, where the substituents are independently selected from: hydroxy, cyano, halogen, and trifluoromethyl,
(b) halogen,
(c) xe2x80x94OC1-6 alkyl,
(d) trifluoromethyl,
(e) hydroxy,
(f) xe2x80x94NO2,
(g) xe2x80x94(CH2)pS(O)kxe2x80x94(C1-6 alkyl), wherein p is 0, 1 or 2,
(h) xe2x80x94(CH2)pS(O)j-NH2,
(i) xe2x80x94(CH2)pS(O)j-NH(C6 alkyl),
(j) xe2x80x94(CH2)pS(O)j-NHR1-6,
(k) xe2x80x94(CH2)pS(O)j-NR6xe2x80x94(C1-6 alkyl),
(l) xe2x80x94(CH2)pCONH2,
(m) xe2x80x94(CH2)pCONHxe2x80x94(C1-6 alkyl),
(n) xe2x80x94(CH2)pCONHR6,
(o) xe2x80x94(CH2)pCONR6xe2x80x94(C1-6 alkyl),
(p) xe2x80x94(CH2)pCO2H,
(q) xe2x80x94(CH2)pCO2xe2x80x94(C1-6 alkyl),
(r) xe2x80x94(CH2)pNR6R7,
(s) xe2x80x94(CH2)pNHxe2x80x94C(O)xe2x80x94C1-6alkyl,
(t) xe2x80x94(CH2)pNHxe2x80x94C(O)xe2x80x94NH2,
(u) xe2x80x94(CH2)pNHxe2x80x94C(O)xe2x80x94NHC1-6alkyl,
(v) xe2x80x94(CH2)pNHxe2x80x94C(O)xe2x80x94N(C1-6 alkyl)2,
(w) xe2x80x94(CH2)pNHxe2x80x94S(O)k-C1-6alkyl,
(x) xe2x80x94(CH2)pN(C1-3alkyl)xe2x80x94C(O)xe2x80x94N(diC1-6 alkyl),
(y) xe2x80x94(CH2)p-heteroaryl, xe2x80x94C(O)-heteroaryl or
xe2x80x94(CH2)pxe2x80x94O-heteroaryl , wherein the heteroaryl is selected from the group consisting of:
(1xe2x80x2) benzimidazolyl,
(2xe2x80x2) benzofuranyl,
(3xe2x80x2) benzothiophenyl,
(4xe2x80x2) benzoxazolyl,
(5xe2x80x2) furanyl,
(6xe2x80x2) imidazolyl,
(7xe2x80x2) indolyl,
(8xe2x80x2) isooxazolyl,
(9xe2x80x2) isothiazolyl,
(10xe2x80x2) oxadiazolyl,
(11xe2x80x2) oxazolyl,
(12xe2x80x2) pyrazinyl,
(13xe2x80x2) pyrazolyl,
(14xe2x80x2) pyridyl,
(15xe2x80x2) pyrimidyl,
(16xe2x80x2) pyrrolyl,
(17xe2x80x2) quinolyl,
(18xe2x80x2) tetrazolyl,
(19xe2x80x2) thiadiazolyl,
(20xe2x80x2) thiazolyl,
(21xe2x80x2) thienyl,
(22xe2x80x2) triazolyl,
(23xe2x80x2) dihydrobenzimidazolyl,
(24xe2x80x2) dihydrobenzofuranyl,
(25xe2x80x2) dihydrobenzothiophenyl,
(26xe2x80x2) dihydrobenzoxazolyl,
(27xe2x80x2) dihydrofuranyl
(28xe2x80x2) dihydroimidazolyl,
(29xe2x80x2) dihydroindolyl,
(30xe2x80x2) dihydroisooxazolyl,
(31xe2x80x2) dihydroisothiazolyl,
(32xe2x80x2) dihydrooxadiazolyl,
(33xe2x80x2) dihydropyrazinyl,
(34xe2x80x2) dihydropyrazolyl,
(35xe2x80x2) dihydropyridinyl,
(36xe2x80x2) dihydropyrimidinyl,
(37xe2x80x2) dihydroquinolinyl,
xe2x80x83wherein the heteroaryl group of items (1xe2x80x2) to (37xe2x80x2) is unsubstituted, or mono, di or tri-substituted, where the substituents are selected from:
(axe2x80x2) hydrogen,
(bxe2x80x2) C1-6 alkyl, branched or unbranched, unsubstituted or mono or di-substituted, where the substituents are selected from: hydrogen and hydroxy,
(cxe2x80x2) hydroxy,
(dxe2x80x2) oxo,
(exe2x80x2) xe2x80x94OR6,
(fxe2x80x2) halogen,
(gxe2x80x2) trifluoromethyl,
(hxe2x80x2) nitro,
(ixe2x80x2) cyano,
(jxe2x80x2) xe2x80x94NHR6,
(kxe2x80x2) xe2x80x94NR6R7,
(lxe2x80x2) xe2x80x94NHCOR6,
(mxe2x80x2) xe2x80x94NR6COR7,
(nxe2x80x2) xe2x80x94NHCO2R6,
(oxe2x80x2) xe2x80x94NR6CO2R7,
(pxe2x80x2) xe2x80x94NHS(O)jR6,
(qxe2x80x2) xe2x80x94NR6S(O)jR7,
(rxe2x80x2) xe2x80x94CONR6R7,
(sxe2x80x2) xe2x80x94COR6,
(txe2x80x2) xe2x80x94CO2R6, and
(uxe2x80x2) xe2x80x94S(O)jR6;
R6 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl,
(3) substituted C1-6 alkyl, where the substituents are independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
(d) cyano,
(e) halogen,
(f) trifluoromethyl, and
(g) C5-8 cycloalkyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(a) hydroxy,
(b) C1-6alkyl,
(c) cyano,
(d) halogen, and
(e) trifluoromethyl;
R7 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl or C5-8 cycloalkyl,
(3) substituted C1-6 alkyl or C5-8 cycloalkyl, where the substituents are independently selected from:
(a) phenyl,
(b) mono, di or tri-substituted phenyl, where the substituent is independently selected from:
(1xe2x80x2) hydroxy,
(2xe2x80x2) C1-3alkyl,
(3xe2x80x2) cyano,
(4xe2x80x2) halogen,
(5xe2x80x2) trifluoromethyl, and
(6xe2x80x2) C1-3alkyloxy,
(c) hydroxy,
(d) oxo,
(e) cyano,
(f) halogen, and
(g) trifluoromethyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(a) hydroxy,
(b) C1-6alkyl,
(c) C1-6alkoxy
(d) cyano,
(e) halogen, and
(f) trifluoromethyl;
or R6 and R7 may be joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or di-substituted, the substituents independently selected from:
(1) hydroxy,
(2) oxo,
(3) cyano,
(4) halogen,
(5) trifluoromethyl,
R8 is selected from the group consisting of:
(1) C2-10 alkenyl,
(2) C2-10 alkynyl,
(3) heteroaryl,
(3) substituted C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, where the substituents are independently selected from:
(a) C3-4 cycloalkyl,
(b) hydroxy,
(c) C1-6 alkyloxy,
(d) cyano,
(e) heteroaryl,
(f) halogen,
(g) trifluoromethyl,
(h) xe2x80x94CO2H,
(i) xe2x80x94SO3H,
(j) xe2x80x94CO2R6,
(k) xe2x80x94CONR6R7,
(l) xe2x80x94NR4CONR6R7,
(m) xe2x80x94NR4CO2R6,
(n) xe2x80x94NR4COR6, and
(o) xe2x80x94SR4;
m is an integer selected from 0, 1 and 2,
n is an integer selected from 0, 1 and 2,
and pharmaceutically acceptable salts thereof.
Preferred compounds of the present invention include those of formula Ia: 
wherein:
R1 is selected from a group consisting of:
C3, C4, C5, C6, C7, or C8 linear or branched alkyl, which is unsubstituted or mono, di or tri-substituted, where the substituents are independently selected from:
(a) hydroxy,
(b) Cl or F,
(c) phenyl,
(d) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(1xe2x80x2) phenyl,
(2xe2x80x2) hydroxy,
(3xe2x80x2) C1-6alkyl,
(4xe2x80x2) cyano,
(5xe2x80x2) halogen, and
(6xe2x80x2) trifluoromethyl,
(e) xe2x80x94NR6COxe2x80x94R7, wherein R6 is hydrogen or C1-6 alkyl, unsubstituted or substituted with C5-8 cycloalkyl, and R7 is C1-6 alkyl, benzyl or phenyl which is unsubstituted or substituted with halo, CF3, C1-6alkyl, or C1-3alkoxy,
(f) xe2x80x94COR7,
(g) xe2x80x94OR7,
(h) xe2x80x94NR6S(O)j-R7, where j is 1 or 2,
(i) xe2x80x94NR6S(O)j-heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1xe2x80x2) benzimidazolyl,
(2xe2x80x2) benzofuranyl,
(3xe2x80x2) benzothiophenyl,
(4xe2x80x2) benzoxazolyl,
(5xe2x80x2) furanyl,
(6xe2x80x2) imidazolyl,
(7xe2x80x2) indolyl,
(8xe2x80x2) isooxazolyl,
(9xe2x80x2) isothiazolyl,
(10xe2x80x2) oxadiazolyl,
(11xe2x80x2) oxazolyl,
(12xe2x80x2) pyrazinyl,
(13xe2x80x2) pyrazolyl,
(14xe2x80x2) pyridyl,
(15xe2x80x2) pyrimidyl,
(16xe2x80x2) pyrrolyl,
(17xe2x80x2) quinolyl,
(18xe2x80x2) tetrazolyl,
(19xe2x80x2) thiadiazolyl,
(20xe2x80x2) thiazolyl,
(21xe2x80x2) thienyl,
(22xe2x80x2) triazolyl,
(23xe2x80x2) dihydrobenzimidazolyl,
(24xe2x80x2) dihydrobenzofuranyl,
(25xe2x80x2) dihydrobenzothiophenyl,
(26xe2x80x2) dihydrobenzoxazolyl,
(27xe2x80x2) dihydrofuranyl
(28xe2x80x2) dihydroimidazolyl,
(29xe2x80x2) dihydroindolyl,
(30xe2x80x2) dihydroisooxazolyl,
(31xe2x80x2) dihydroisothiazolyl,
(32xe2x80x2) dihydrooxadiazolyl,
(33xe2x80x2) dihydropyrazinyl,
(34xe2x80x2) dihydropyrazolyl,
(35xe2x80x2) dihydropyridinyl,
(36xe2x80x2) dihydropyrimidinyl,
(37xe2x80x2) dihydroquinolinyl,
xe2x80x83wherein the heteroaryl is unsubstituted or mono di or tri-substituted, where the substituents are independently selected from:
(axe2x80x2) phenyl,
(bxe2x80x2) hydroxy,
(cxe2x80x2) oxo,
(dxe2x80x2) cyano,
(exe2x80x2) halogen,
(fxe2x80x2) C1-6alkyl,and
(gxe2x80x2) trifluoromethyl;
R2 is selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) C1-6 alkyl,
(4) xe2x80x94Oxe2x80x94C1-6 alkyl,
(5) phenyl,
(6) xe2x80x94N(CH3)xe2x80x94COxe2x80x94N(H)(CH3),
(7) xe2x80x94N(H)xe2x80x94COxe2x80x94Oxe2x80x94CH3, and
(8) xe2x80x94COxe2x80x94CH3;
R3 is selected from the group consisting of:
(1) xe2x80x94N(R8)xe2x80x94COxe2x80x94Oxe2x80x94(C1-6 alkyl)xe2x80x94Ar, and
(2) xe2x80x94N(R8)xe2x80x94COxe2x80x94Oxe2x80x94R7;
Ar is selected from the group consisting of:
(1) phenyl,
(2) pyrazinyl,
(3) pyrazolyl,
(4) pyridyl,
(5) pyrimidyl, and
(6) thienyl,
xe2x80x83wherein the Ar is unsubstituted or mono or di-substituted, and the substituents are independently selected from:
(a) C1-6 alkyl, unsubstituted or substituted with
(1xe2x80x2) oxo,
(2xe2x80x2) hydroxy,
(3xe2x80x2)xe2x80x94OR7,
(4xe2x80x2) phenyl, and
(5xe2x80x2) trifluoromethyl,
(b) halogen,
(c) xe2x80x94OC1-6 alkyl,
(d) trifluoromethyl,
(e) xe2x80x94NO2,
(f) CONR6xe2x80x94(C1-2 alkyl),
(g) CO2H,
(h) CO2xe2x80x94(C1-2 alkyl),
(i) CH2NR6xe2x80x94(C1-2 alkyl),
(j) CH2NHxe2x80x94C(O)xe2x80x94C1-3alkyl,
(k) CH2NHxe2x80x94C(O)NH2,
(l) CH2NHxe2x80x94C(O)NHC1-3alkyl,
(m) CH2NHxe2x80x94C(O)N-diC1-3 alkyl),
(n) CH2NHxe2x80x94S(O)j-C1-3alkyl,
(o) CH2-heteroaryl, with the heteroaryl is selected from the group consisting of:
(1xe2x80x2) imidazolyl,
(2xe2x80x2) oxazolyl,
(3xe2x80x2) pyridyl,
(4xe2x80x2) tetrazolyl,
(5xe2x80x2) triazolyl,
and the heteroaryl is unsubstituted, mono, di or tri-substituted, where the substituents selected from:
(axe2x80x2) hydrogen,
(bxe2x80x2) C1-6 alkyl, branched or unbranched, unsubstituted or mono or di-substituted, the substituents being selected from hydrogen and hydroxy;
R8 is selected from the group consisting of:
(1) C2-10 alkenyl,
(2) C2-10 alkynyl,
(3) heteroaryl,
(4) substituted C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl,
xe2x80x83where the substituents are independently selected from:
(a) C3-4 cycloalkyl,
(b) hydroxy,
(c) C1-6 alkyloxy,
(d) cyano,
(e) heteroaryl,
(f) halogen,
(g) trifluoromethyl,
(h) xe2x80x94CO2H,
(i) xe2x80x94SO3H,
(j) xe2x80x94CO2R6,
(k) xe2x80x94CONR6R7,
(l) xe2x80x94NR4CONR6R7,
(m) xe2x80x94NR4CO2R6,
(n) xe2x80x94NR4COR6, and
(o) xe2x80x94SR4;
m is an integer selected from 0, 1 and 2,
n is an integer selected from 0, 1 and 2, with the proviso that the sum of
m+n is 2;
and pharmaceutically acceptable salts thereof.
More preferred compounds of the present invention include those of formula Ib: 
wherein:
R1, R2 and R3 are as defined herein;
and pharmaceutically acceptable salts thereof.
In the present invention it is preferred that
R1 is selected from the group consisting of:
C3, C4, C5, C6, C7, or C8 linear or branched alkyl, which is unsubstituted or mono, di or tri-substituted, where the substituents are independently selected from:
(a) hydroxy,
(b) Cl or F,
(c) phenyl,
(d) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(1xe2x80x2) phenyl,
(2xe2x80x2) hydroxy,
(3xe2x80x2) C1-6alkyl,
(4xe2x80x2) cyano,
(5xe2x80x2) halogen, and
(6xe2x80x2) trifluoromethyl,
(e) xe2x80x94NR6COxe2x80x94R7, wherein R6 is hydrogen or C1-6 alkyl, unsubstituted or substituted with C5-8 cycloalkyl, and R7 is C1-6 alkyl, benzyl or phenyl which is unsubstituted or substituted with halo, CF3, C1-6alkyl, or C1-3alkoxy,
(f) xe2x80x94COR7,
(g) xe2x80x94OR7,
(h) xe2x80x94NR6S(O)j-R7, where j is 1 or 2,
(i) xe2x80x94NR6S(O)j-heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1xe2x80x2) benzimidazolyl,
(2xe2x80x2) benzofuranyl,
(3xe2x80x2) benzoxazolyl,
(4xe2x80x2) furanyl,
(5xe2x80x2) imidazolyl,
(6xe2x80x2) indolyl,
(7xe2x80x2) isooxazolyl,
(8xe2x80x2) isothiazolyl,
(9xe2x80x2) oxadiazolyl,
(10xe2x80x2) oxazolyl,
(11xe2x80x2) pyrazinyl,
(12xe2x80x2) pyrazolyl,
(13xe2x80x2) pyridyl,
(14xe2x80x2) pyrimidyl,
(15xe2x80x2) pyrrolyl,
(16xe2x80x2) quinolyl,
(17xe2x80x2) tetrazolyl,
(18xe2x80x2) thiadiazolyl,
(19xe2x80x2) thiazolyl,
(20xe2x80x2) thienyl, and
(21xe2x80x2) triazolyl,
xe2x80x83wherein the heteroaryl is unsubstituted or mono di or tri-substituted, where the substituents are independently selected from:
(axe2x80x2) phenyl,
(bxe2x80x2) hydroxy,
(cxe2x80x2) oxo,
(dxe2x80x2) cyano,
(exe2x80x2) halogen,
(fxe2x80x2) C1-6alkyl,and
(gxe2x80x2) trifluoromethyl.
In the present invention it is preferred that
R1 bears at least one substituent which is selected from:
(a) xe2x80x94NR6COxe2x80x94R7, wherein R6 is C1-6 alkyl, unsubstituted or substituted with cyclohexyl, and R7 is C1-6 alkyl, benzyl or phenyl which is unsubstituted or substituted with halo, CF3, C1-3alkyl, or C1-3alkoxy, and
(b) xe2x80x94NR6S(O)j-R7, where j is 1 or 2.
In the present invention it is more preferred that
R1 is selected from the group consisting of:
C4, C5, C6, C7 or C8 linear or branched alkyl, which is mono, di- or tri-substituted, where the substituents are independently selected from:
(a) hydroxy,
(b) Cl or F,
(c) phenyl,
(d) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(1xe2x80x2) hydroxy,
(2xe2x80x2) methyl or ethyl,
(3xe2x80x2) Cl or F, and
(4xe2x80x2) trifluoromethyl,
(e) xe2x80x94NR6COxe2x80x94R7, wherein R6 is C1-3 alkyl, unsubstituted or substituted with cyclohexyl, and R7 is C1-6 alkyl, benzyl or phenyl which is unsubstituted or substituted with halo, CF3, C1-3alkyl, or C1-3alkoxy,
(f) xe2x80x94NR6S(O)j-R7, where j is 1 or 2.
In the present invention it is still more preferred that
R1 is selected from the group consisting of:
C4, C5, or C6 linear alkyl, which is substituted, where the substituents are independently selected from:
(a) phenyl,
(b) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(1xe2x80x2) hydroxy,
(2xe2x80x2) methyl or ethyl,
(3xe2x80x2) Cl or F, and
(4xe2x80x2) trifluoromethyl,
(c) C1-6 alkyl,
(d) xe2x80x94NR6COxe2x80x94R7, wherein R6 is methyl, unsubstituted or substituted with cyclohexyl, and R7 is phenyl which is unsubstituted or substituted with Cl, F, CF3, C1-3alkyl or C1-3alkoxy, and
(e) xe2x80x94NR6S(O)j-R7, where j is 1 or 2.
In the present invention it is still more preferred that
R1 is C4 linear alkyl, which is substituted, where the substituents are independently selected from:
(a) phenyl,
(b) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(1xe2x80x2) hydroxy,
(2xe2x80x2) methyl or ethyl,
(3xe2x80x2) Cl or F, and
(4xe2x80x2) trifluoromethyl,
(c) C1-6 alkyl, and
(d) xe2x80x94NR6S(O)j-R7, where R6 is methyl, unsubstituted or substituted with cyclohexyl, and R7 is phenyl which is unsubstituted or substituted with Cl, F, CF3, C1-3alkyl or C1-3alkoxy, and j is 1 or 2.
In the present invention it is even more preferred that
R1 is: 
xe2x80x83wherein:
B is selected from the group consisting of:
(a) phenyl, and
(b) di or tri-substituted phenyl, wherein the substituents on phenyl are independently selected from: chloro, methyl, phenyl, C1-3alkoxy, and CF3;
R6 is C1-3 alkyl, unsubstituted or substituted with cyclohexyl;
R10 is selected from the group consisting of:
(1) hydrogen, and
(2) C1-6 alkyl;
R11 and R12 are independently selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) methyl or ethyl,
(4) Cl or F, and
(5) trifluoromethyl.
In the present invention it is most preferred that
R1 is selected from the group consisting of: 
In the present invention it is most preferred that
R1 is selected from the group consisting of: 
In the present invention it is preferred that
R2 is selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) C1-6 alkyl,
(4) xe2x80x94Oxe2x80x94C1-6 alkyl, and
(5) phenyl.
In the present invention it is more preferred that
R2 is selected from the group consisting of:
(1) hydrogen,
(2) hydroxy, and
(3) phenyl.
In the present invention it is most preferred that
R2 is hydrogen.
In the present invention it is preferred that
Ar is selected from the group consisting of:
(1) phenyl,
(2) pyrazinyl,
(3) pyrazolyl,
(4) pyridyl,
(5) pyrimidyl, and
(6) thienyl,
xe2x80x83wherein the Ar is unsubstituted or mono or di-substituted, and substituents are independently selected from:
(a) C1-3 alkyl, unsubstituted or substituted with
(1xe2x80x2) oxo,
(2xe2x80x2) hydroxy,
(3xe2x80x2) xe2x80x94OR7,
(4xe2x80x2) phenyl, and
(5xe2x80x2) trifluoromethyl,
(b) xe2x80x94NO2,
(c) xe2x80x94CONH2,
(d) xe2x80x94CONR6xe2x80x94(C1-2 alkyl),
(e) xe2x80x94CO2H,
(f) xe2x80x94CO2xe2x80x94(C1-2 alkyl),
(g) xe2x80x94CH2NR6xe2x80x94(C1-2 alkyl),
(h) xe2x80x94CH2NHxe2x80x94C(O)xe2x80x94C1-3alkyl,
(i) xe2x80x94CH2NHxe2x80x94C(O)NH2,
(j) xe2x80x94CH2NHxe2x80x94C(O)NHC1-3alkyl,
(k) xe2x80x94CH2NHxe2x80x94C(O)N-diC1-3 alkyl),
(l) xe2x80x94CH2NHxe2x80x94S(O)j-C1-3alkyl,
(m) xe2x80x94CH2-heteroaryl, with the heteroaryl is selected from the group consisting of:
(1xe2x80x2) imidazolyl,
(2xe2x80x2) oxazolyl,
(3xe2x80x2) pyridyl,
(4xe2x80x2) tetrazolyl,
(5xe2x80x2) triazolyl,
and the heteroaryl is unsubstituted, mono, di or tri-substituted, where the substituents selected from:
(axe2x80x2) hydrogen,
(bxe2x80x2) C1-6 alkyl, branched or unbranched, unsubstituted or mono or di-substituted, the substituents being selected from hydrogen and hydroxy.
In the present invention it is more preferred that
Ar is selected from:
xe2x80x83phenyl, mono substituted phenyl or di-substituted phenyl, wherein the substituents are selected from the group consisting of:
(a) C1-3 alkyl, unsubstituted or substituted with
(1xe2x80x2) oxo,
(2xe2x80x2) hydroxy, or
(3xe2x80x2) xe2x80x94OR6, wherein R6 is hydrogen or C1-3 alkyl,
(b) xe2x80x94NO2,
(c) xe2x80x94CONH2,
(d) xe2x80x94CO2H,
(e) xe2x80x94CH2NR6xe2x80x94(C1-2 alkyl),
(f) xe2x80x94CH2NHxe2x80x94C(O)xe2x80x94C1-3alkyl,
(g) xe2x80x94CH2NHxe2x80x94C(O)NH2,
(h) xe2x80x94CH2NHxe2x80x94C(O)NHC1-3alkyl,
(i) xe2x80x94CH2NHxe2x80x94C(O)N-diC1-3 alkyl),
(j) xe2x80x94CH2NHxe2x80x94S(O)j-C1-3alkyl, and
(k) xe2x80x94CH2-heteroaryl, where heteroaryl is selected from the group consisting of:
(1xe2x80x2) imidazolyl,
(2xe2x80x2) oxazolyl,
(3xe2x80x2) pyridyl,
(4xe2x80x2) tetrazolyl,
(5xe2x80x2) triazolyl,
and where heteroaryl is unsubstituted, mono, di or tri substituted, where the substituents are independently selected from:
(axe2x80x2) hydrogen,
(bxe2x80x2) C1-6 alkyl, branched or unbranched, unsubstituted or mono or disubstituted, where the substituents are selected from: hydrogen and hydroxy.
In the present invention it is even more preferred that
Ar is selected from:
phenyl, or mono substituted phenyl wherein the substituent is selected from: xe2x80x94NO2, xe2x80x94CONH2, and xe2x80x94CO2H.
In the present invention it is even more preferred that
Ar is selected from:
phenyl, or para-NO2 phenyl.
In the present invention it is preferred that
R3 is:
xe2x80x94N(R8)xe2x80x94COxe2x80x94Oxe2x80x94(C1-6 alkyl)-Ar.
In the present invention it is more preferred that
R3 is:
xe2x80x94N(R8)xe2x80x94COxe2x80x94Oxe2x80x94(CH2)xe2x80x94Ar.
In the present invention it is still more preferred that
R3 is selected from:
(1) xe2x80x94N(R8)xe2x80x94COxe2x80x94Oxe2x80x94(CH2)-phenyl,
(2) xe2x80x94N(R8)xe2x80x94COxe2x80x94Oxe2x80x94(CH2)-(phenyl-NO2),
(3) xe2x80x94N(R8)xe2x80x94COxe2x80x94Oxe2x80x94(CH2)-(phenyl-CONH2), and
(4) xe2x80x94N(R8)xe2x80x94COxe2x80x94Oxe2x80x94(CH2)-(phenyl-CO2H).
In the present invention it is preferred that
R8 is selected from the group consisting of:
(1) C2-10 alkenyl,
(2) C2-10 alkynyl,
(3) heteroaryl,
(4) substituted C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, where the substituents are independently selected from:
(a) C3-4 cycloalkyl,
(b) hydroxy,
(c) C1-6 alkyloxy,
(d) cyano,
(e) heteroaryl,
(f) halogen,
(g) xe2x80x94CO2H,
(h) xe2x80x94CO2R6, and
(i) xe2x80x94CONR6R7.
In the present invention it is more preferred that
R8 is selected from the group consisting of:
(1) C2-10 alkenyl,
(2) C2-10 alkynyl,
(3) substituted C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl,
xe2x80x83where the substituents are independently selected from:
(a) C3-4 cycloalkyl,
(b) hydroxy,
(c) C1-6 alkyloxy,
(d) cyano,
(e) tetrazolyl,
(f) fluoro,
(g) xe2x80x94CO2H,
(h) xe2x80x94CO2R6, and
(i) xe2x80x94CONR6R7.
In the present invention it is even more preferred that
R8 is selected from the group consisting of:
(1) C3-5 alkenyl,
(2) C3-4 alkynyl,
(3) substituted C1-4 alkyl, where the substituents are independently selected from:
(a) cyclopropyl,
(b) cyclobutyl,
(c) cyano,
(d) fluoro,
(e) xe2x80x94CO2CH3,
(f) xe2x80x94CONH2,
(g) C1-2 alkyloxy, and
(h) hydroxy.
In the present invention it is still more preferred that
R8 is selected from the group consisting of:
(1) xe2x80x94CH2xe2x80x94CHxe2x95x90CH2,
(2) xe2x80x94(CH2)2xe2x80x94CHxe2x95x90CH2,
(3) xe2x80x94(CH2)3xe2x80x94CHxe2x95x90CH2,
(4) xe2x80x94CH2xe2x80x94Cxe2x89xa1CH,
(5) xe2x80x94CH2xe2x80x94Cxe2x89xa1N,
(6) xe2x80x94CH2-cyclopropyl,
(7) xe2x80x94CH2-cyclobutyl,
(8) xe2x80x94(CH2)2xe2x80x94F,
(9) xe2x80x94CH2xe2x80x94CO2xe2x80x94CH3,
(10) xe2x80x94CH2xe2x80x94COxe2x80x94NH2,
(11) xe2x80x94(CH2)2xe2x80x94OCH3,
(12) xe2x80x94(CH2)2xe2x80x94OH,
(13) xe2x80x94(CH2)3xe2x80x94OH, and
(14) xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OH.
In the present invention it is preferred that
m is an integer selected from 0, 1 and 2,
n is an integer selected from 0, 1 and 2, with the proviso that the sum of
m+n is 2.
In the present invention it is more preferred that
m is 1, and n is 1.
As appreciated by those of skill in the art, halo as used herein are intended to include chloro, fluoro, bromo and iodo. Similarly, C1-6, as in C1-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5, or 6 carbons, such that C1-6alkyl specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, and cyclohexyl.
Exemplifying the invention is the use of the compounds disclosed in the Examples and herein.
Preferred compounds of the present invention include the compounds of the formula: 
wherein:
and pharmaceutically acceptable salts thereof.
Specific compounds within the present invention include a compound which selected from the group consisting of: 
and pharmaceutically acceptable salts thereof.
For use in medicine, the salts of the compounds of the present invention will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts such as those formed with hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
The pharmaceutically acceptable salts of the present invention may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope solvates of the compounds of formula I and salts thereof, for example, hydrates.
The compounds according to the invention may have one or more asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The subject compounds are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound. Exemplifying the invention is the use of the compounds disclosed in the Examples and elsewhere herein.
The present invention is directed to the use of the foregoing compounds as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4. These compounds are particularly useful as modulators of the chemokine receptors CCR-3 or CCR-5, and especially useful as modulators of the chemokine receptor CCR-5.
The utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assay for CCR-1 and/or CCR-5 binding as disclosed by Van Riper, et al., J. Exp. Med., 177, 851-856 (1993), and the assay for CCR-2 and/or CCR-3 binding as disclosed by Daugherty, et al., J. Exp. Med., 183, 2349-2354 (1996). Cell lines for expressing the receptor of interest include those naturally expressing the receptor, such as EOL-3 or THP-1, or a cell engineered to express a recombinant receptor, such as CHO, RBL-2H3, HEK-293. For example, a CCR3 transfected AML14.3D10 cell line has been placed on restricted deposit with American Type Culture Collection in Rockville, Md. as ATCC No. CRL-12079, on Apr. 5, 1996. The utility of the compounds in accordance with the present invention as inhibitors of the spread of HIV infection in cells may be demonstrated by methodology known in the art, such as the HIV quantitation assay disclosed by Nunberg, et al., J. Virology, 65 (9), 4887-4892 (1991).
In particular, the compounds of the following examples had activity in binding to the CCR-5 receptor in the aforementioned assays, generally with an IC50 of less than about 10 xcexcM. Such a result is indicative of the intrinsic activity of the compounds in use as modulators of chemokine receptor activity.
Mammalian chemokine receptors provide a target for interfering with or promoting eosinophil and/or lymphocyte function in a mammal, such as a human. Compounds which inhibit or promote chemokine receptor function, are particularly useful for modulating eosinophil and/or lymphocyte function for therapeutic purposes. Accordingly, the present invention is directed to compounds which are useful in the prevention and/or treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
For example, an instant compound which inhibits one or more functions of a mammalian chemokine receptor (e.g., a human chemokine receptor) may be administered to inhibit (i.e., reduce or prevent) inflammation. As a result, one or more inflammatory processes, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited. For example, eosinophilic infiltration to inflammatory sites (e.g., in asthma) can be inhibited according to the present method.
Similarly, an instant compound which promotes one or more functions of a mammalian chemokine receptor (e.g., a human chemokine) is administered to stimulate (induce or enhance) an inflammatory response, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes. For example, eosinophils can be recruited to combat parasitic infections.
In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
Diseases and conditions associated with inflammation and infection can be treated using the method of the present invention. In a preferred embodiment, the disease or condition is one in which the actions of eosinophils and/or lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response.
Diseases or conditions of humans or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler""s syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren""s syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet""s disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn""s disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin or organs. Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis.
Diseases or conditions of humans or other species which can be treated with promoters of chemokine receptor function, include, but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due congenital deficiency in receptor function or other causes; and infectious diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms); (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis); trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceral worms, visceral larva migrans (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larva migrans (Ancylostona braziliense, Ancylostoma caninum).
The compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases.
In another aspect, the instant invention may be used to evaluate putative specific agonists or antagonists of chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4. Accordingly, the present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds which modulate the activity of chemokine receptors. For example, the compounds of this invention are useful for isolating receptor mutants, which are excellent screening tools for more potent compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition. The compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and CXCR-4. As appreciated in the art, thorough evaluation of specific agonists and antagonists of the above chemokine receptors has been hampered by the lack of availability of non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors. Thus the compounds of this invention are commercial products to be sold for these purposes.
The present invention is further directed to a method for the manufacture of a medicament for modulating chemokine receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
The present invention is further directed to the use of these compounds in the prevention or treatment of infection by a retrovirus, in particular, the human immunodeficiency virus (HIV) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. In addition, a compound of the present invention may be used for the prevention of infection by HIV and the prevention of AIDS, such as in post-coital prophylaxis or in the prevention of maternal transmission of the HIV virus to a fetus or a child upon birth.
In a preferred aspect of the present invention, a subject compound may be used in a method of inhibiting the binding of a human immunodeficiency virus to a chemokine receptor, such as CCR-5 and/or CXCR-4, of a target cell, which comprises contacting the target cell with an amount of the compound which is effective at inhibiting the binding of the virus to the chemokine receptor.
The subject treated in the methods above is a mammal, preferably a human being, male or female, in whom modulation of chemokine receptor activity is desired. xe2x80x9cModulationxe2x80x9d as used herein is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism. In particular, the compounds of the present invention have been found to exhibit primarily antagonism of chemokine receptor activity. The term xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
The term xe2x80x9ccompositionxe2x80x9d as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The terms xe2x80x9cadministration ofxe2x80x9d and or xe2x80x9cadministering axe2x80x9d compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
Combined therapy to modulate chemokine receptor activity and thereby prevent and treat inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities.
For example, in the treatment or prevention of inflammation, the present compounds may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the pressent invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. Examples of other active ingredients that may be combined with a compound of the present. invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists such as those described in U.S. Pat. No. 5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96/22966, WO96/20216, WO96/01644, WO96/06108, WO95/15973 and WO96/31206; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines (H1-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidal anti-asthmatics such as xcex22-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors of phosphodiesterase type IV (PDE-IV); (i) other antagonists of the chemokine receptors, especially CCR-1, CCR-2, CCR-3 and CCR-5; (j) cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; (k) anti-diabetic agents such as insulin, sulfonylureas, biguanides (metformin), xcex1-glucosidase inhibitors (acarbose) and glitazones (troglitazone and pioglitazone); (l) preparations of interferon beta (interferon beta-1xcex1, interferon beta-1xcex2); (m) other compounds such as 5-aminosalicylic acid and prodrugs thereof, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents. The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
The present invention is further directed to combinations of the present compounds with one or more agents useful in the prevention or treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art.
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-Nxe2x80x2-(t-butylcarboxamido)-piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. Pat. No. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz. The preparation of ddC, ddI and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of The present invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
In the treatment or prevention of conditions which require chemokine receptor modulation an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made from known procedures or as illustrated. 
The compounds of the present invention are prepared by alkylating heterocycle I under appropriate conditions to provide compound II (Scheme 1). The required starting materials for preparing heterocycle I are available commercially or can be prepared using the methods given below.
Thus, heterocycle I is combined with the appropriate aldehyde and the intermediate imine or iminium species is reduced to the tertiary amine chemically (e.g. using, sodium cyanoborohydride, sodium borohydride, or sodium triacetoxyborohydride) or catalytically (e.g. using hydrogen and palladium on carbon or Raney nickel catalyst) (Scheme 1). The aldehyde needed for this reaction can be prepared by methods generally known in the chemical literature; for the purposes of the present invention one preparation of a representative aldehyde is described in Hale, J. J.; Finke, P. E.; MacCoss, M. Bioorganic and Medicinal Chemistry Letters 1993,3, 319-322.
In an alternative embodiment of the present invention, heterocycle I can be alkylated with an alkyl halide or alkyl sulfonate ester (with or without an added base to neutralize the mineral acid or sulfonic acid by-product) to give the desired compound (Scheme 1). The alkyl halide or alkyl sulfonate needed for this reaction can be prepared by methods generally known in the chemical literature; for the purposes of the present invention an aldehyde, prepared as described above, can be reduced to an alcohol with sodium borohydride, diisobutylaluminum hydride or lithium aluminum hydride, and the product alcohol converted to either the alkyl halide using methods described in March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, pp. 431-433 (1992), or alkyl sulfonate ester using methods described in March J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, p. 498-499 (1992).
In an alternative embodiment of the present invention, I can be acylated to give a tertiary amide; subsequent reduction with a strong reducing agent (e.g. diborane; borane in THF; borane dimethylsulfide, or lithium aluminum hydride) will give the desired compound (Scheme 1). The acylating agent needed for this reaction can be prepared by methods generally known in the chemical literature; for the purposes of the present invention an aldehyde, prepared as described above, can be oxidized using such commonly used reagents as permanganate in acid or silver oxide, and the resulting acid activated as an acid chloride or mixed anhydride which can be used to acylate I. The product amide can in and of itself be a chemokine receptor modulator or can be reduced as noted above to give the tertiary amine.
Optionally, compound II may be further modified in subsequent reactions, as illustrated below. 
In an alternative embodiment of the present invention, compounds of interest can be prepared by activating the hydroxyl groups of 1,4-dihydroxy-2-butyne, for example by treatment with triphenylphosphine dibromide in acetonitrile, to give 1,4-dibromo-2-butyne (Scheme 2). Displacement of one bromide with the sodium salt of an arylsulfonamide (wherein Rs and Rt are substituents on the phenyl or Ar as defined herein), followed by displacement of the other bromide with a suitable cyclic secondary amine, provides the acetylene derivative. III. Palladium-catalysed hydrostannylation preferentially forms the 3-tributylstannyl olefin IV. The minor product from this reaction can also isolated and carried through the sequence described below. Compound IV can be converted to the corresponding 3-aryl derivative V by treatment with an aryl bromide (wherein Rx, Ry and Rz are substituents on the phenyl or heteroaryl as defined herein) in the presence of a suitable palladium catalyst at or above room temperature. Suitable catalysts include palladium acetate and triphenylphosphine, bis(triphenylphosphine) palladium (II) chloride, or palladium (0) bis(dibenzylidineacetone) in the presence of triphenylphosphine or tri-2-furylphosphine. Suitable solvents include 1,4-dioxane, DMF, and N-methylpyrrolidinone. A base such as potassium carbonate or potassium phosphate may also be employed. Compound V may be employed as a chemokine receptor modulator itself or it can be reduced to saturated derivative VI by standard conditions, for example catalytic hydrogenation with palladium on carbon or with palladium hydroxide in the presence of a mild acid such as acetic acid. 
In an alternative embodiment of the present invention, the allyl acid VII (prepared, for example, as described in Hale et al; see above) can be converted into the N-methyl-N-methoxy amide VIII, which is then treated with an alkyl or aryl metal reagent, for example methyllithium or butyllithium, to provide the ketone IX (Scheme 3). The ketone can be converted into an imine which can then be reduced to secondary amine X chemically, (e.g using sodium cyanoborohydride or sodium borohydride), or catalytically (e.g. using hydrogen and palladium on carbon or Raney nickel catalyst). Acylation under standard conditions, for example with an acid chloride, provides the corresponding amide. Alternatively, amine X can be sulfonylated, for example with a alkyl or aryl sulfonyl chloride or an alkyl or aryl sulfonic anhydride, to give (for aryl substituted sulfonylating reagents) sulfonamide XI. The allyl group in XI can be oxidatively cleaved to aldehyde XII with osmium tetroxide followed by sodium periodate or with ozone at low temperature. Reductive amination of aldehyde XII with azacycle I can then be carried out under the conditions described above to give the desired product XIII. 
Preparation of hydroxymethyl derivatives of the target compounds is outlined in Scheme 4. The oxazolidinone imide XV is prepared from acid XIV, by formation of the corresponding acid chloride (by treatment with oxalyl chloride or thionyl chloride) and addition of N-lithio 2(S)-benzyl oxazolidinone. The enolate azidation can be accomplished by a variety of methods, such as the procedure of Evans, D. A.; et. al. J. Am. Chem. Soc. 1990, 112, 4011-4030. Reduction of the oxazolidinone moiety of XVI can be carried out by a variety of metal hydride reagents (e.g. LiBH4/MeOH, LiAlH4, etc.). The azide is then reduced by treatment with PPh3/H2O to provide alcohol XVII. Formation of cyclic carbamate XVIII is accomplished by literature methods; i.e. phosgene, triphosgene or carbonyl dumidazole, followed by N-alkylation with sodium hydride and methyl iodide. The target compounds are prepared by oxidative cleavage of the olefin to the aldehyde followed by reductive amination with an amine salt as described for Scheme 1, to provide XIX. Hydrolysis of the cyclic carbamate under basic conditions (for example, potassium hydroxide in ethanol at elevated temperature) followed by selective amide formation at 0xc2x0 C. by combining with an acylating agent or a sulfonating agent such as an arylsulfonyl chloride gives the corresponding hydroxyamides or hydroxysulfonamides (i.e. XX). 
Compounds with alternate arrangements of an amide bond are prepared as shown in Scheme 5. Acid VII can be homologated under Arndt-Eistert conditions to give the chain-extended acid XIV, which can be derivatized under standard acylating conditions with, for example, an aniline derivative, to give the amide XI. Oxidative cleavage of the olefin with osmium tetroxide or ozone then provides aldehyde XII as an intermediate suitable for coupling as described earlier. 
In addition, ketone derivatives are prepared by an extension of the chemistry given above, as shown in Scheme 6. An Arndt-Eistert chain extension of acid XIV provides heptenoic acid XXIII, which after conversion into N-methoxy-N-methyl amide XXIV, can be reacted with an aryl organometallic reagent, such as an aryl magnesium bromide, to provide ketone XXV. Routine oxidative cleavage then gives the desired aldehyde XXVI, which can be coupled with an appropriate amine as described above. 
Alcohol containing compounds are prepared according to procedures given in Scheme 7. Formation of the N-methyl-N-methoxy amide of acid VII followed by oxidative cleavage of the olefin provides intermediate aldehyde XXVII. Coupling with an appropriate amine provides amide XXVIII. Addition of an organometallic reagent to compound XXVIII provides illustrated ketone XXIX. Treatment with a hydride reducing agent, such as sodium borohydride, then yields the desired alcohol XXX. 
Formation of heterocycle compounds is carried out according to the procedure given in Scheme 8 for substituted imidazoles. Reduction of allyl acid VII with a strong reducing agent such as lithium aluminum hydride provides alcohol XXXI. In situ formation of the trifluoromethanesulfonate ester of the formed alcohol allows for displacement of the triflate with a nucleophile such as 2-phenylimidazole, to give imidazole XXXII. Oxidative cleavage under standard conditions provides the aldehyde XXIII which can then be coupled under the conditions described above to the appropriate amine. 
Compounds with ether substituents are prepared by the route shown in Scheme 9. Thus, allyl acid VII can be reduced to alcohol XXXI with, for example, lithium aluminum hydride. This alcohol can be alkylated by a Williamson ether synthesis, by deprotonation with a strong base such as sodium hydride or sodium hexamethyldisilazide followed by reaction with a benzyl halide such as benzyl bromide. The resulting ether XXXIV can be processed through the oxidative cleavage steps described earlier to provide aldehyde XXXV. This aldehyde can then be coupled with an appropriate amine under reductive amination conditions to give XXXVI. Alternatively, reduction of XXXV to the corresponding alcohol followed by conversion to the bromide allows for alkylation with an amine to provide XXXVI. 
The substituted amines employed in the preceding Schemes can be obtained commercially in many cases or are prepared by a number of procedures. For example, as shown in Scheme 10, compound XXXVII, the N-t-butoxycarbonyl protected form of isonipecotic acid (4-piperidinecarboxylic acid) can be activated under standard conditions, for example with a carbodiimide, and converted into ester XXXVIII or amide XXXIX. Alternatively, acid XXXVII can be converted into the N-methyl-N-methoxy amide, XL, which upon reaction with organomagnesium and organolithium reagents forms the ketone XLI. The Boc group of XXXVIII, XXXIX and XLI can be removed under acidic conditions to provide secondary amines XLII, XLIII and XLIV, respectively. 
Alternatively, CBZ-protected piperidine XLV can be allowed to react with oxalyl chloride and then sodium azide, to provide the corresponding acyl azide, which can then be thermally rearranged to isocyanate XLVI (Scheme 11). Compound XLVI can be treated with an alcohol ROH or an amine RRxe2x80x2NH to form carbamate XLVII or urea XLVIII, respectively, each of which can be deprotected with hydrogen in the presence of palladium on carbon to secondary amines XLIX or L. 
If the carbamate XLVII has R=xe2x80x94(CH2)xCH2Cl, where x=1-3, then treatment with a suitable base, such as sodium hydride, lithium hexamethyldisilazide or potassium t-butoxide, can induce cyclization to compound LI (Scheme 12). For other R groups, carbamate XLVII can be treated with an alkylating agent Rxe2x80x2X,where Rxe2x80x2=primary or secondary alkyl, allyl, propargyl or benzyl, while X=bromide, iodide, tosylate, mesylate or trifluoromethanesulfonate, in the presence of a suitable base, such as sodium hydride, lithium hexamethyldisilazide or potassium t-butoxide, to give derivative LII. In each case, removal of the CBZ protecting group under standard conditions provides the secondary amines LIII and LIV. 
Additional derivatives of a piperidine with nitrogen functionality at C4 can be carried out as shown in Scheme 13. For example, if the ring nitrogen is protected with a CBZ group, as with isocyanate XLVI, treatment with tert-butyl alcohol in the presence of copper(I) chloride, provides Boc derivative LV. This compound can be selectively deprotected to the free amine LVI. This amine can be acylated with an acid chloride, a chloroformate, an isocyanate, or a carbamyl chloride, to provide compounds LVII, XLVII or XLVIII. Alternatively, amine LVI can be sulfonated with an alkyl or arylsulfonyl chloride, to give sulfonamide LVIII. 
In each case, removal of the CBZ group under reductive conditions gives the desired secondary amines LIX, XLIX, L, and LX (Scheme 14). 
Functionalization of the piperdine can alson be carried out after it has been coupled with an N1 substituent. For example, as shown in Scheme 15, reductive deprotective of CBZ derivative LV yields secondary amine LXI. Reductive amination with an appropriate aldehyde fragment (as described above) provides piperidine LXII. Removal of the Boc group under acidic conditions then gives primary amine LXIII. This primary amine can then be functionalized by analogy to the chemistry given in Scheme 13. Compound LXI can also be alkylated as described above in Scheme 12, and then carried though the remaining sequence given in Scheme 15. 
A method of preparing a backbone with an alternate spacing from the one described above is given in Scheme 16. Deprotonation of a suitable phenylacetonitrile derivative LXI with sodium hydride followed by addition of allyl bromide provides the allyl nitrile LXV. Reduction to the corresponding aldehyde LXVI is carried out with diisobutylaluminum hydride in THF. Reductive amination with a primary amine followed by sulfonylation then provides sulfonamide LXVII. Selective hydroboration of the terminal position of the olefin, for example with 9-BBN, followed by oxidation with basic hydrogen peroxide, then gives primary alcohol LXVIII. Conversion of this alcohol to the corresponding bromide with triphenylphosphine-dibromide complex followed by alkylation with a cyclic secondary amine then gives the desired product LXIX. 
Another backbone variation is prepared according to Scheme 17. Epoxidation of a suitably substituted styrene derivative LXX with an oxidizing agent such as mCPBA provides-the epoxide LXXI which is converted to the aminoalcohol LXXII by treatment with a primary amine RNH2. Treatment of LXXII with an acylating agent or a sulfonylating agent under mild conditions (as shown for the conversion to compound LXXIII) produces the corresponding neutral alcohol. Activation of the hydroxy group with, for example, methanesulfonyl chloride, followed by treatment with a secondary cyclic amine yields the aminosulfonamide LXXIV. 
Another backbone variation is prepared according to Scheme 18. Treatment of 3-arylpentane-1,5-dioic acid LXXV with acetic anhydride in toluene provides anhydride LXXVI. Addition of an amine RNH2 yields amidoacid LXXVII, which can be reduced with a strong reducing agent like lithium aluminum hydride to give aminoalcohol LXXVIII. Selective sulfonylation on nitrogen can be accomplished by treatment with a suitable arylsulfonyl chloride, to produce sulfonamide LXXIX. Activation of the hydroxy group with methanesulfonyl chloride in the presence of triethylamine followed by addition of a cyclic secondary amine in isobutyronitrile in the presence of sodium carbonate at elevated temperatures then provides the desired sulfonamidoamine LXXX. 
Another backbone variation is prepared according to Scheme 19. Reduction of 2-arylmalonic acid derivative LXXXI with lithium aluminum hydride provides diol LXXXII, which upon treatment with sodium hydride and t-butyldimethylsilyl chloride in THF produces selectively the monosilyl ether LXXXIII. Exposure of this compound to an N-substituted arylsulfonamide in the presence of DEAD and triphenylphosphine in THF provides the sulfonamide LXXXIV. Removal of the silyl group, for example with tetrabutylammonium fluoride in THF, followed by treatment with methanesulfonyl chloride in ethyl acetate, yields the mesylate LXXXV. Treatment of this mesylate with a cyclic secondary amine then provides the desired product LXXXVI. 
Another backbone variation is prepared according to Scheme 20. Reductive alkylation of the commercially available aldehyde LXXXVII with a suitable primary amine followed by sulfonylation provides sulfonamide LXXXVIII. Treatment of this olefin with osmium tetroxide followed by sodium periodate provides aldehyde LXXXIX. Reductive amination with a cyclic secondary amine then provides the target compound XC. 
Additional derivatives of a piperidine with nitrogen functionality at C4 can be carried out as shown in Scheme 21. Treatment of commerically available 4 bromopiperidine XCI with a suitable nitrogen protecting agent, such as di-t-butyl pyrocarbonate, under standard conditions, provides protected piperidine XCII. Treatment with sodium azide (or another suitable salt of hydrazoic acid) in DMF at between room temperature and reflux provides the azide XCIII. Reduction of the azide under standard conditions, for example by catalytic hydrogenation with palladium on carbon or with triphenylphosphine and a proton source, provides primary amine XCIV, which can be employed in the same way as compound LVI (in Scheme 13) (subject to chosing functionality which is compatible with the conditions required for the removal of the t-butoxycarbonyl group). Alternatively, XCIV can be carried forward by acylation, for example with carbobenzyloxy chloride, to provide carbamate XCV. Alkylation of XCV under basic conditions with an alkylating agent containing a primary, secondary, allylic, propargylic, or benzylic leaving group, such as a chloride, bromide, iodide, or alkyl- or aryl-sulfonate ester, provides carbamate XCVI, which can be deprotected under standard acidic conditions to provide the piperidine XCVII. 
Additional derivatives of a piperidine with nitrogen functionality at C4 can be carried out as shown in Scheme 22. Reductive amination of N-Boc protected 4-piperidone XCVIII under standard conditions provides amine XCIX. Standard acylation can then be carried out, for example with carbobenzyloxy chloride, which provides XCVI. Removal of the Boc group under standard acidic conditions then provides piperidine XCVII. 
Refunctionalization of subunits on the carbamate group on the piperidine ring can also be carried out. For example, as shown in Scheme 23, the N-allyl carbamate C can be dihydroxylated with osmium tetroxide under standard conditions to provide diol CI. Compound C can also be converted to the primary alcohol CII by treatment with an appropriate hydroborating agent, such as 9-borabicyclononane, followed by oxidation with hydrogen peroxide or trimethylamine N-oxide.
In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.